The document discusses lung cancer, including: 1) Lung cancer incidence and mortality rates have increased in China since 1990, becoming the leading cause of cancer death. 2) Risk factors for lung cancer include cigarette smoking, air pollution, certain occupations, and genetic factors. 3) Diagnosis involves imaging like chest X-rays and CT scans, as well as procedures like bronchoscopy to obtain tissue samples. 4) Treatment depends on cancer type and stage, and may involve surgery, chemotherapy, radiation therapy, targeted therapy, and other approaches. Adjuvant chemotherapy provides a limited survival benefit for non-small cell lung cancer.

1. 肺 癌 LUNG CANCER 中山大学肿瘤医院 王 思 愚

2. Lung cancer – China incidence and mortality rates (1990-2009) 90 年后肺癌占恶性肿瘤死因第 1 位的省市 : 上 海 : 43.53/10 万 天 津 : 38.86 辽 宁 : 32.07 黑龙江 : 29.06 吉 林 : 28.06 云 南 : 23.07 北 京 : 22.25 内蒙古 : 22.04

5. lung cancer cases diagnosed in Cancer Center of Sun Yat-sen University

6. lung cancer cases diagnosed in Cancer Center of Sun Yat-sen University

7. Etiology of Lung Cancer Cigarette smoking FHIT gene Air pollutions and ionizing radiation Occupational associations asbestos, uranium( in miners), arsenical fumes, nickel, radon gas Oncogenes and suppressor genes ras,myc,bcl-2,c-erbB-2 p53,RB

8. The risk of lung cancer after stoping smoking Garfinkel L, Silverberg E. CA Cancer J Clin. 1991;41:137-145.

9. Classifications According to anatomy Central lung cancer: mostly is squamous and small cell carcinoma. Peripheral lung cancer: mostly is adenous. According to histologic classification -- SCLC (15-20%) --NSCLC (80-85%) includes squamous 、 large cell, adenocarcinoma, adenosquamous . Squamous Non-squamous

11. Clinical Manifestations Development and symptoms usually asymptomatic :early stage of the lung cancer Cough: invasion of small bronchi hemoptysis: erosion into vessels chest pain: invasion of the pleura, chest wall, or mediastinum dyspnea and fever :obstruct airway: pleural effusion :invasion of the pleura Other symptoms : inappetence , weight loss

12. Clinical Manifestations Paraneoplasic syndromes associated with brochogenic carcinoma often stem from release of the following hormones: ① ADH (syndrome of inappropriate antidiuretic hormone reslease). ② ATCH (Cushing’s syndrome). ③ Parathormone or PGE (hypercalcemia). ④ Calcitionin (hypocalcemia).

13. Other paraneoplastic syndromes include myopathy, peripheral neuropathy, acanthosis nigricans, and hypertrophic pulmonary osteoarthropathy (clubbing of fingers).

14. Diagnosis of lung cancer requires: A: detecting the tumor. B: establish the cell type. C: define the stage of the tumor. determing cell type is the most important because it influences the treatment !

16. Physical examinations Usually in early stage, most of the patients with lung cancer have no positive physical findings. General findings include abnormal percussion, breath sounds changes, moist rales (when pneumonia happens) Digital clubbing, superior vena cava syndrome, horner’s syndrome (unilaterally constricted pupil, enophthalmos, narrowed palpebral fissure and loss of sweating on the same side of the face.

17. Physical examinations Endobronchial obstruction may result in a localized wheeze Lobar collapse may result in an area of decreased breath sounds and dullness to percussion.

18. Chest X-ray It is the most important method to find lung cancer. If a patient with chronic cough, sputum with few blood, and dyspnea, lower fever he should adopt a chest X-ray. The most frequent finding is a mass in the lung field.

19. chest X-ray Secondary manifestations include lobar collapse, pleural effusion, pneumonitis, elevation of the hemidiaphragm, hilar and mediastinal adenopathy, and erosion of ribs or vertebrae due to metastases.

22. Lung cancer on CT CT is the most useful in evaluating patients with pulmonary and mediastinal masses. It is also useful for detecting multiple metastases. CT can show a mass to be located in which lobe of lung field and the size of the mass. It also shows the nodule in the mediastinum. Sometimes, when a mass locate behind the heart, chest X-ray can`t detect it .CT can detect some secret sites of lung cancer.

24. Bronchoscopy It is important both for determining if a tumor is present and for obtaining tissue for histologic diagnosis. Usually, the combination of bronchial brushing and forceps biopsy is positive 90 to 93 percent of the tumors located in proximal airway.

25. Transbronchial lung biopsy It may be utilized when tumor located in peripheral airway. Transthoracic needle with guidance by CT can be used to detect lesions located near the chest wall

27. 2008 年 8 月 28 日

28. Bronchoscopy

29. Pathology NSCLC: squamous cell carcinoma

30. 2008 年 11 月 19 日

31. What should we do before treament ? Histology classification SCLC NSCLC Staging Treatment based on Evidenced Medicine Follow up plan

32. Staging of lung cancer TNM stage: CTNM, PTNM T: Primary Tumor (TX, T0) T1, T2, T3, T4 N: Nodal Involvement N0, N1, N2, N3 M: Distant metastasis M0, M1 The relationship of clinical stage and TNM stage Staging of small cell lung cancer limited stage extensive stage .

33. Stage process Chest CT (include adrenal gland ) Bone scan Magnetic resounce imaging (MRI) PET: positron emission tomograpy Bronchoscopic techniques Video-assisted thoracic surgery

34. Stage grouping Mountain CF. Chest. 1997;111:1710-1717. IIIB IIIB IIIB IIIB N3 IIIB IIIA IIIA IIIA N2 IIIB IIIA IIB IIA N1 IIIB IIB IB IA N0 T4 T3 T2 T1

36. Treatment Including: A: Surgery B: Chemotherapy C: Radiation therapy D: Targeted therapy E: Some other therapy immunologic therapy chinese medicine

37. Surgery Non-small cell lung cancer: patients with stage I and II are considered candidates for surgical resection, with stage III cancer may be candidates for surgery.

38. Surgery More than 90 percent of small cell lung cancer has often metastasized at the time of diagnosis. So these patients usually adopt radiation therapy or chemotherapy before surgery. We must measure pulmonary function before surgical therapy.

39. 5-years survival rate after surgery Mountain CF ， Chest 1997. TNM stage 5 YS （ clinical stage ） 5YS （ pathologic stage ） T1 N0 M0 n=687 61% n=511 67% T2 N0 M0 n=1189 38% n=549 57% T1 N1 M0 n=29 34% n=76 55% T2 N1 M0 n=250 24% n=288 39% T3 N0 M0 n=107 22% n=87 38% T3 N1 M0 n=40 9% n=55 25% T1-3 N2 M0 n=471 13% n=344 23% T4 N0-2 M0 n=458 7% NA Any T N3 M0 n=572 3% NA Any T any N M1 n=1427 1% NA

40. Radiation therapy Radiotherapy plays a major role in the treatment of lung cancer. It is divided into curative treatment and palliative treatment. It is of proven benefit in controlling bone pain, spinal cord compression, superior vena cava syndrome and bronchial obstruction.

41. Chemotherapy Non-small cell lung cancer Adjuvant chem. Chem. for stage IV disease Small-cell lung cancer it is highly responsive to chemotherapy.

42. The newest evidence for Adjuvant chemotherapy

43. 2007 update meta-analysis

44. 2007’s ASCO

45. LACE meta-analysis ： OS HR=0.89 95%CI=0.82-0.96 P=0.005 Pignon JP, et al. J Clin Oncol 2008; 26:3552-3559 100 80 60 40 20 0 1 2 3 4 5 ≥ 6 Time From Randomization (years) Chem. Control 总体生存 (%)

46. LACE meta-analysis ： DFS HR=0.84 95%CI=0.78-0.91 P<0.001 Pignon JP, et al. J Clin Oncol 2008; 26:3552-3559. Time From Randomization (years) 100 80 60 40 20 0 1 2 3 4 5 ≥ 6 Chem. Control 无病生存 (%)

47. LACE meta-analysis ： Survival according to type of death. Decreases lung cancer–related death (HR=0.83, 95%CI=0.76-0.90, P<0.001) Increase noncancer-related death (HR=1.36, 95%CI=1.10-1.69, P=0.004) 主要出现在前 6 个月 (HR=2.41, 95%CI=1.64-3.55, P<0.001) Pignon JP, et al. J Clin Oncol 2008; 26:3552-3559.[ 临床肿瘤学杂志中文版 2009; 3(1): 10-17.] 100 80 60 40 20 0 1 2 3 4 5 ≥ 6 Time From Randomization (years) Survival (%) Chem. ( noncancer-related death ) Cont (noncancer-related death ) 化疗 ( 癌症相关死亡 ) 不化疗 ( 癌症相关死亡 )

49. IIIA-N2:Overall survival at 5 years with chemotherapy improved by 12% 31.1% vs 19.1% MS:33m vs 24m

50. Questions ： Why the benefits of adjuvant chemotherapy is limited ？ The direction of our following research: - Do we continue to adopt chemotherapy to all patients just for the improved 6%-12% total survival rate ？ - Or can we pick out those patients who is sensitive to adjuvant chemotherapy ,then the other patients can avoid the unnecessary toxicity of chemotherapy.

52. Chemotherapy for advanced stage of lung cancer BMJ, 1995

53. NSCLC Meta-analyses NSCLC Meta-analyses Collaborative Group. JCO 2008; 26:4617-25 .[ 临床肿瘤学杂志中文版 2009; 3(2): 45.] 16 项 RCT 2714 例患者 IPD 资料 HR=0.77 95%CI=0.71-0.83 P≤0.0001 1YS: 29% vs. 20% 1.0 0.8 0.6 0.4 0.2 0 3 6 9 12 15 18 21 24 时间 ( 月 ) 概率 事件数 患者总数 1240 1293 1315 1399 SC+CT 仅 SC

54. First-line chemotherapy options in NSCLC (E1594): comparable efficacy with platinum doublets Schiller, et al. NEJM 2002 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 Time (months) Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel Probability of survival Therapeutic plateau: overall survival <12 months

55. Overall Survival by Histology Non-squamous (n=481) Squamous (n=182) HR=0.70 (95% CI: 0.56-0.88) P =0.002 HR=1.07 (95% CI: 0.49–0.73) P =0.678 Survival Probability Time (months) Time (months) 2009 ASCO Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 10.3 mos Placebo 10.8 mos

56. Targeted therapy Such as epidermal growth factor receptor inhibitors, angiogenesis inhibitors and apoptosis inducers ects.

60. 晚期非小细胞肺癌 front-line 治疗策略 EGFR 突变者 30 ％ TKI MST ： 20 － 24 月 EGFR 野生者 70 ％ 腺癌 35 ％ 鳞癌 35 ％ 第三代＋铂类 10 月 维持治疗 13 月 培美曲塞＋铂类： 11.8 月 西妥昔单抗 或贝伐单抗 12 － 16 月 + ERCC1 BRCA1: 选择铂类药物 RRMI ：选择 Gemcitabine TS ：选择 Pemetrexed

61. Treatment of Lung Cancer NSCLC Ⅰ ,Ⅱ,N0N1 of Ⅲa stage: surgery + adjuvant chemotherapy for those patients who is N0-1 and had radical resection of lung cancer, adjuvant radiotherapy is not only inefficacy but do harm to patients. N2 of ⅢA stage: neoadjuvant chemotherapy Ⅲ B stage: chemotherapy + radiotherapy (surgery when it is needed.) Ⅳ stage: chemotherapy and targeted therapy. SCLC limited stage: chemotherapy + surgery / radiotherapy -- chemotherapy extensive stage : chiefly chemotherapy

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